1. Field of the Invention
The present invention relates to 5-nitrobenzofurans, to a process for preparing 5-nitrobenzofurans, as well as to 5-nitro-2,3-dihydrobenzofuran-3-ols, to a process for the preparation thereof and to their intermediates.
2. Brief Description of the Invention
Benzofurans have acquired industrial importance in particular as intermediates for preparing medicaments. The benzofuran structure is found for example in anti-arrhythmic active ingredients such as, for example, amiodarone and bufuralol.
2-(n-butyl)-5-nitrobenzofuran is used as intermediate in the preparation of dronedarone (N-[2-(n-butyl)-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]methanesulfonamide), which likewise has anti-arrhythmic activity.
EP-A 0 471 609 describes a process for preparing 2-(n-butyl)-5-nitrobenzofuran which starts from 2-hydroxy-5-nitrobenzyl bromide. This involves reaction with triphenylphosphane initially to prepare 2-hydroxy-5-nitrobenzyltriphenyl-phosphonium bromide, which is acylated with pentanoyl chloride in the presence of an amine base and subsequently cyclized to 2-(n-butyl)-5-nitrobenzofuran. The disadvantages of this process are the costly precursor 2-hydroxy-5-nitrobenzyl bromide, the low yield and the large amounts of waste, in particular of triphenylphosphane oxide.
WO-A 01/28974 and WO-A 01/29019 disclose processes for preparing 5-nitrobenzofurans, starting from salicylaldehyde, and proceeding in a four-stage synthesis via 2-(2-formyl-4-nitrophenoxy) carboxylic acids as intermediates. The disadvantages of this process are the cost of salicylaldehyde, and the fact that the oxidation-sensitive aldehyde functionality is present in all intermediates.
In a further process disclosed in EP-A 1 116 719, 5-nitro-2(3H)-benzofuranone is reacted in the presence of pentanoic acid and pentanoic anhydride to give 3-(1-hydroxypentylidene)-5-nitro-2(3H)-benzofuranone which reacts under acidic conditions to give 2-(n-butyl)-5-nitrobenzofuran. The disadvantage of this process is that 5-nitro-2(3H)-benzofuranone is used as precursor, which makes industrial application uneconomic.
There was thus a continuing need to develop an efficient and widely applicable process for preparing 5-nitrobenzofuranones which both starts from low-cost, easily obtainable precursors and can easily be implemented industrially.